VASCULAR NA+-PUMP ACTIVITY AND HYPERTENSION

血管 NA 泵活动和高血压

• 批准号: 3343615
• 负责人: Emel Songu-Mize
• 金额: $ 8.51万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3343615
• 关键词: adenosinetriphosphatase; adrenal hypertension; desoxycorticosterone; digitalis; disease /disorder model; enzyme inhibitors; familial hypertension; laboratory rat; molecular pathology; monoclonal antibody; neurogenic hypertension; vascular smooth muscle

The long term objective of this project is to define the mechanisms underlying changes in Na. K-ATPase (NKA), or the Na-Pump (NaP), activity in vascular smooth muscle in development and maintenance of hypertension. Tail artery NaP activity, measured as ouabain-sensitive Rb uptake, shows tri- phasic changes in DOCA-salt hypertension. An endogenous inhibitor of the pump contributes to these changes. To determine whether the alterations in NaP are associated with changes in the kinetic properties of the vascular NaP, we will measure the km and V max of the vascular NaP during early, established, and late stages of DOCA-salt hypertension. We will also quantitate the NaP sites using a monoclonal antibody against NKA. An endogenous digitalis-like inhibitor(s) of the vascular NaP may be important in development and maintenance of hypertension. To further define the relationships between chronic exposure to a circulating NaP inhibitor, alterations in vascular NaP activity and development of hypertension, ASI- 222 (a polar analog of digitalis, 10 times more potent an inhibitor of NKA than digoxin) will be administered to inhibit chronically the vascular NaP. Preliminary experiments show that chronic iv administration of ASI-222 produces hypertension. Studies will be conducted to determine whether chronic exposure to a circulating NaP inhibitor produces hypertension and alterations in vascular NaP activity and NaP site density comparable to those seen in the DOCA-salt model, which is characterized by a circulating endogenous NaP inhibitor. There are two major limitations of the DOCA-salt hypertensive model in the study of NaP activity determinants; I) it is difficult to study the NKA enzyme activity in vascular tissue because the arteries contain small amounts of this enzyme, and 2) there are other confounding variables inherent to an in vivo system which complicate a focuses and in-depth study of vascular NaP function/NKA activity regulation by endogenous and/or exogenous inhibitors. To overcome these limitations, cultured vascular smooth muscle cells will be used to define the direct effects of chronic NaP inhibition on regulation of NaP/NKA. Effects of plasma or plasma extracts treated with DOCA-salt and ASI-222 will be compared. Additionally, effects or certain long-chain unsaturated fatty acids known to inhibit NKA, and which are possible candidate(s) for an endogenous inhibitor of the NaP, will be studied.

该项目的长期目标是确定机制 钠的潜在变化。K-ATPase(NKA)或钠泵(NAP)的活性 血管平滑肌在高血压的发生和维持中的作用尾巴 动脉NAP活性，作为哇巴因敏感的Rb摄取，显示三个 DOCA-盐性高血压的时相变化。一种内源性血管紧张素转换酶抑制剂 泵促成了这些变化。以确定是否发生了变化 NAP与血管运动特性的变化有关 Nap，我们将在早期测量血管Nap的Km和Vmax， 确诊的和晚期的DOCA-盐性高血压。我们还将 用抗NKA的单抗对NAP位点进行定量。 血管NAP的内源性洋地黄样抑制物(S)可能是 对高血压的发展和维持很重要。为了进一步定义 慢性暴露于循环中的NAP抑制剂， 血管NAP活性的改变与高血压的发生、发展 222(洋地黄的极性类似物，是NKA抑制剂的10倍 比地高辛)将被用来慢性抑制血管午睡。 初步实验表明，慢性静脉注射ASI-222 会产生高血压。将进行研究以确定是否 长期接触循环中的NAP抑制剂会产生高血压和 血管午睡活动和午睡部位密度的变化可与 在DOCA-SALT模型中看到的那些，该模型的特征是循环 内源性NAP抑制物。 DOCA-SALT高血压模型有两个主要局限性 NAP活性决定因素的研究；I)NKA的研究是困难的 血管组织中的酶活性，因为动脉含有少量的 这种酶的量，以及2)还有其他令人困惑的变量 体内系统所固有的，这使焦点和深入研究复杂化 内源性和/或对血管NAP功能/NKA活性的调节 外源抑制物。为了克服这些限制，培养的血管 平滑肌细胞将被用来定义慢性支气管炎的直接影响 NAP抑制NAP/NKA的调节。血浆或血浆的影响 用DOCA-盐和ASI-222处理的提取物将进行比较。另外， 或某些已知的抑制NKA的长链不饱和脂肪酸的作用， 以及哪些是NAP内源性抑制物的可能候选者(S)， 将会被研究。